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Title: S100a4-Cre-mediated deletion of Ptch1 causes hypogonadotropic hypogonadism: Role of pituitary hematopoietic cells in endocrine regulation

Author
item REN, YI - BAYLOR COLLEGE OF MEDICINE
item MONKKONEN, TERESA - UNIVERSITY OF CALIFORNIA
item LEWIS, MICHAEL - BAYLOR COLLEGE OF MEDICINE
item BERNARD, DANIEL - McGILL UNIVERSITY - CANADA
item CHRISTIAN, HELEN - UNIVERSITY OF OXFORD
item JORGEZ, CAROLINA - BAYLOR COLLEGE OF MEDICINE
item MOORE, JOSHUA - BAYLOR COLLEGE OF MEDICINE
item LANDUA, JOHN - BAYLOR COLLEGE OF MEDICINE
item CHIN, HAELEE - RICE UNIVERSITY
item CHEN, WEIQIN - AUGUSTA UNIVERSITY
item SINGH, SWARNIMA - BAYLOR COLLEGE OF MEDICINE
item KIM, IK - BAYLOR COLLEGE OF MEDICINE
item ZHANG, XIANG - BAYLOR COLLEGE OF MEDICINE
item XIA, YAN - BAYLOR COLLEGE OF MEDICINE
item PHILLIPS, KEVIN - BAYLOR COLLEGE OF MEDICINE
item MACKAY, HARRY - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item WATERLAND, ROBERT - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item LJUNGBERT, CECILIA - BAYLOR COLLEGE OF MEDICINE
item SAHA, PRADIP - BAYLOR COLLEGE OF MEDICINE
item HARTIG, SEAN - BAYLOR COLLEGE OF MEDICINE
item COLL, TATIANA - UNIVERSIDAD NACIONAL AUTONOMA DE MEXICO

Submitted to: JCI Insight
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/13/2019
Publication Date: 7/2/2019
Citation: Ren, Y.A., Monkkonen, T., Lewis, M.T., Bernard, D.J., Christian, H.C., Jorgez, C.J., Moore, J.A., Landua, J.D., Chin, H.M., Chen, W., Singh, S., Kim, I.S., Zhang, X.F., Xia, Y., Phillips, K.J., Mackay, H., Waterland, R.A., Ljungbert, C., Saha, P.K., Hartig, S.M., Coll, T.F. 2019. S100a4-Cre-mediated deletion of Ptch1 causes hypogonadotropic hypogonadism: Role of pituitary hematopoietic cells in endocrine regulation. Journal of Clinical Immunology Insights (JCI Insights). e126325. https://doi.org/10.1172/jci.insight.126325.
DOI: https://doi.org/10.1172/jci.insight.126325

Interpretive Summary: Hormones produced by the anterior pituitary gland regulate an array of important physiological functions, but the causes of pituitary hormone disorders are not fully understood. To better understand pituitary endocrinologic development, we generated mice lacking the critical cell-signaling receptor Patched1 in just one specific cell type in the anterior pituitary – S100a4 expressing cells. We found that, during the pubertal transition (i.e. sexual maturation), specific mice of both sexes develop markedly small gonads (hypogonadism). We characterized the S100a4-expressing cells in the pituitary and found that most of them appear to be a specialized type of immune cells called folliculostellate cells. Our results point to a previously unrecognized role of immune cells in the pituitary in regulating pituitary development and pituitary hormone disorders.

Technical Abstract: Hormones produced by the anterior pituitary gland regulate an array of important physiological functions, but the causes of pituitary hormone disorders are not fully understood. Herein we report that genetically engineered mice with deletion of the hedgehog signaling receptor PATCHED1 (Ptch1) by S100a4 promoter–driven Cre recombinase (S100a4-Cre;Ptch1fl/fl mutants) exhibit adult-onset hypogonadotropic hypogonadism and multiple pituitary hormone disorders. During the transition from puberty to adulthood, S100a4-Cre;Ptch1fl/fl mice of both sexes develop hypogonadism coupled with reduced gonadotropin levels. Their pituitary glands also display severe structural and functional abnormalities, as revealed by transmission electron microscopy and expression of key genes regulating pituitary endocrine functions. S100a4-Cre activity in the anterior pituitary gland is restricted to CD45+ cells of hematopoietic origin, including folliculo-stellate cells and other immune cell types, causing sex-specific changes in the expression of genes regulating the local microenvironment of the anterior pituitary. These findings provide in vivo evidence for the importance of pituitary hematopoietic cells in regulating fertility and endocrine function, in particular during sexual maturation and likely through sexually dimorphic mechanisms. These findings support a previously unrecognized role of hematopoietic cells in causing hypogonadotropic hypogonadism and provide inroads into the molecular and cellular basis for pituitary hormone disorders in humans.